Drug-Drug Interactions of 257 Antineoplastic and Supportive Care Agents With 7 Anticoagulants: A Comprehensive Review of Interactions and Mechanisms.

Data on drug-drug interactions (DDI) of antineoplastic drugs with anticoagulants is scarce. We aim to evaluate factors associated with DDI of antineoplastic and supportive care drugs with anticoagulants resulting in modification of pharmacokinetics of these last mentioned. A literature review on DDI databases and summaries of products characteristics (SmPC) was done. Drug-drug interactions of 257 antineoplastic and supportive care drugs with direct oral anticoagulants (DOACs), warfarin, enoxaparin, or fondaparinux were categorized as no clinically significant expected DDI, potentially weak DDI, potentially clinically significant DDI, and recommendation against coadministration. Logistic regression models were performed to analyze the association between the dependent variable potentially clinically significant interaction/recommendation against coadministration and the mechanisms of DDI. Of the 1799 associations, 84.4% were absence of DDI, 3.6% potentially weak DDI, 10.2% potentially clinically relevant DDI, and 2.0% recommendation against coadministration. Warfarin has higher DDI potential than other anticoagulants. Enoxaparin and fondaparinux have fewer DDI than others. There was no difference between DOACs. Drug-drug interactions with apixaban and rivaroxaban was independently associated with the absence of CYP3A4 competition, P-glycoprotein inhibition, CYP3A4 induction, and drug class of tyrosine kinase inhibitors. Drug-drug interactions with dabigatran and edoxaban was associated with inhibition of P-glycoprotein and tyrosine kinase inhibitors. Warfarin, induction of CYP3A4, and inhibition of CYP2C9. Enoxaparin and fondaparinux, only tyrosine kinase inhibitors. Direct oral anticoagulants did not differ regarding DDI with antineoplastic agents. Warfarin presented more DDI than other anticoagulants. P-glycoprotein inhibition and CYP3A4 induction were independently associated with DDI of antineoplastic agents with DOACs.

Thyrotrophin levels and coronary artery calcification: Cross-sectional results of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

OBJECTIVE: There is little information about the association between thyrotrophin (TSH) levels and coronary artery calcification (CAC). Our aim was to analyse the association between TSH quintiles and subclinical atherosclerosis measured by CAC, using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). DESIGN: Cross-sectional study. PATIENTS: We excluded individuals using medications that affect thyroid function and who self-reported cardiovascular disease. We included euthyroid subjects and individuals with subclinical hypothyroidism (SCHypo) and subclinical hyperthyroidism (SCHyper). Logistic regression models evaluated CAC >100 Agatston units as the dependent variable, and increasing quintiles of TSH as the independent variable, adjusted for demographic and cardiovascular risk factors. RESULTS: Our sample included 3836 subjects, mean age 49 years (interquartile range 44-56); 1999 (52.1%) were female, 3551 (92.6%) were euthyroid, 239 (6.2%) had SCHypo and 46 (1.2%) had SCHyper. The frequency of women, White people and never smokers as well as body mass index and insulin resistance increased according to quintiles. The 1st quintile for TSH (0-0.99 mIU/L) was associated with CAC >100, using the 3rd quintile (1.39-1.85 mIU/L) as reference (adjusted OR=1.57, 95% CI: 1.05-2.35, P=.027), but no association was shown for the 5th quintile (2.68-35.5 mIU/L) compared to the 3rd. Restricting the analysis to euthyroid subjects did not change the results. For women, but not for men, we observed a U-shaped curve with 1st and 5th TSH quintiles associated with CAC>100. CONCLUSION: Low and low-normal (1st quintile) TSH levels were associated with CAC>100 Agatston units in a sample with subclinical thyroid disorders and euthyroid subjects.

Thyrotropin levels are associated with chronic kidney disease among healthy subjects in cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

BACKGROUND: Few studies have evaluated a possible relationship between thyrotropin levels and glomerular filtration rate (GFR) and albumin/creatinine ratio in euthyroid subjects. We aimed to analyze this association using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: Cross-sectionally, we included subjects with normal thyroid function and with subclinical hypothyroidism (SCH). We excluded individuals using medications that affect thyroid function. Linear and logistic regression models evaluated GFR estimated by Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) and albuminuria/creatinine ratio as dependent variables and thyrotropin quartiles in individuals with euthyroidism and SCH as independent variables, adjusted for demographical characteristics and diseases related to CKD. RESULTS: We included 13,193 subjects with a median age of 51 years [interquartile range, (IQR): 45-58], 6840 (51.8%) women, 12,416 (94.1%) euthyroid, and 777 (5.9%) with SCH. SCH subjects were characterized by higher age, triglycerides, frequency of white race, cardiovascular disease, CKD, and former smokers. In adjusted models, log-transformed TSH in euthyroid subjects was inversely and strongly associated with CKD (ß = -2.181, 95% CI -2.714 to -1.648), P < 0.0001 for glomerular filtration rate and 4.528 (1.190-7.865) for albuminuria/creatinine ratio. Multivariate logistic models for euthyroid subjects showed an OR of 1.45 (95% CI 1.15-1.83) for GFR and of 1.95 (95% CI 1.08-3.54) for albuminuria/creatinine ratio in the fourth quartile of TSH using the first as the reference. CONCLUSIONS: Thyrotropin levels are independently associated with CKD in euthyroid subjects.

Lack of Association Between Subclinical Hypothyroidism and Carotid-Femoral Pulse Wave Velocity in a Cross-Sectional Analysis of the ELSA-Brasil.

BACKGROUND: There is little available data on carotid-femoral pulse wave velocity (cf-PWV) in subjects with subclinical hypothyroidism (SCH). We aimed to analyze the association between SCH and cf-PWV using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: We included subjects with normal thyroid function (thyrotropin (TSH): 0.4-4.0 mIU/l, and normal free thyroxine (FT4: 0.8-1.9ng/dl) and SCH (TSH > 4.0 mIU/l and normal FT4) evaluated for cf-PWV in a cross-sectional analysis. We excluded individuals using medications that interfere in thyroid function, antihypertensives, or diuretics, and subjects with chronic kidney disease or previous cardiovascular disease. Generalized linear and logistic regression models evaluated cf-PWV as a dependent variable and SCH as an independent variable, adjusted for cardiovascular risk factors. RESULTS: Of 8,341 subjects (52.3% women), 7,878 (94.4%) were euthyroid and 463 (5.6%) showed SCH. The median age was 50 years (interquartile range: 44-56). The groups differed by age, sex, body mass index, glomerular filtration rate, and C-reactive protein. SCH was not associated with cf-PWV in the full-adjusted linear model (ß = -0.039; P = 0.562) and with cf-PWV >75th percentile in the full-adjusted logistic model (odds ratio = 0.94; 95% confidence interval = 0.72-1.22). CONCLUSION: In a large sample, SCH was not associated with increased cf-PWV.

Thyroid Function and High-Sensitivity C-Reactive Protein in Cross-Sectional Results from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil): Effect of Adiposity and Insulin Resistance.

BACKGROUND: Subclinical hypothyroidism (SCH) is associated with an increased cardiovascular risk, but little information is available about its association with high-sensitivity C-reactive protein (hs-CRP). OBJECTIVES: This study aims to analyze the association between SCH and hs-CRP using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: The study has a cross-sectional design. We included subjects with normal thyroid function (thyroid-stimulating hormone, TSH, 0.4-4.0 µIU/ml and normal free thyroxine, fT4, 10.3-24.45 pmol/l) and SCH (TSH >4.0 µIU/ml and normal fT4) who were evaluated for hs-CRP. We excluded individuals on medications that affect thyroid function and those who had prevalent cardiovascular disease. Multivariate linear regression evaluated hs-CRP and TSH as continuous variables, and logistic regression models assessed hs-CRP ≥19.05 nmol/l as the dependent variable and crescent quintiles of TSH as the independent variables adjusted for demographic and cardiovascular risk factors. RESULTS: We included 12,284 subjects with a median age of 50 years (interquartile range = 45-57); 6,408 (52.2%) were female, 11,589 (94.3%) were euthyroid, and 695 (5.7%) had SCH. Bivariate analyses of participants stratified into quintiles of TSH revealed differences according to hs-CRP but not the Framingham risk score. The fifth quintile of TSH was not associated with elevated hs-CRP, odds ratio = 1.11 (95% confidence interval = 0.98-1.26), p = 0.102, in a fully adjusted logistic model, also consistent with the linear model (ß = 0.024, p = 0.145). CONCLUSIONS: TSH is not associated with hs-CRP. Obesity and insulin resistance are very important confounders in the study of the association between SCH and hs-CRP.